Campus Units

Biochemistry, Biophysics and Molecular Biology

Document Type

Article

Publication Version

Accepted Manuscript

Publication Date

3-2011

Journal or Book Title

Molecular Microbiology

Volume

79

Issue

6

First Page

1594

Last Page

1601

DOI

10.1111/j.1365-2958.2011.07545.x

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of the human disease Tuberculosis, and remains a worldwide health threat responsible for ~1.7 million deaths annually. During infection, Mtb prevents acidification of the engulfing phagosome, thus blocking endocytic progression and eventually leading to stable residence. The diterpenoid metabolite isotuberculosinol (isoTb) exhibits biological activity indicative of a role in this early arrest of phagosome maturation. Presumably, isoTb production should be induced by phagosomal entry. However, the relevant enzymatic genes are not transcriptionally upregulated during engulfment. Previous examination of the initial biosynthetic enzyme (Rv3377c/MtHPS) involved in isoTb biosynthesis revealed striking inhibition by its Mg2+ co-factor, leading to the hypothesis that the depletion of Mg2+ observed upon phagosomal engulfment may act to trigger isoTb biosynthesis. While Mtb is typically grown in relatively high levels of Mg2+ (0.43 mM), shifting Mtb to media with phagosomal levels (0.1 mM) led to a significant (~10-fold) increase in accumulation of the MtHPS product, halimadienyl diphosphate, as well as easily detectable amounts of the derived bioactive isoTb. These results demonstrate isoTb production by Mtb specifically under conditions that mimic phagosomal cation concentrations, and further support a role for isoTb in the Mtb infection process.

Comments

This is the peer reviewed version of the following article: Mann, F. M., VanderVen, B. C. and Peters, R. J. (2011), Magnesium depletion triggers production of an immune modulating diterpenoid in Mycobacterium tuberculosis. Molecular Microbiology, 79: 1594–1601, which has been published in final form at doi:10.1111/j.1365-2958.2011.07545.x. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

Copyright Owner

Blackwell Publishing Ltd

Language

en

File Format

application/pdf